In our hands, the physiologically compromised hmox1 null mice did not survive the initial surgical stress given their fragile baseline phenotype, and we posit that they were therefore unlikely to mount a viable proliferative response. Data presented here would support CO as one mechanism by which HO-1 imparts protection. The other products of HO-1, biliverdin and bilirubin, could also be involved as antioxidants and

signaling molecules, but have not been tested. Based on the effects defined with HO-1, our first question was to determine if CO exposure would impart beneficial effects on liver regeneration after hepatectomy without inflow occlusion. CO induced a more rapid induction of hepatocyte proliferation and maintenance AZD1152 HQPA of primary function, which offers important clinical relevance in situations of massive hepatectomy model37 and small for size transplants.38 Given that fatal hepatic failure in the massive hepatectomy model is characterized by increased apoptosis and inability for hepatocyte replication to sufficiently meet the physiological needs of the animal,39 we predicted

that CO exposure would induce a survival benefit in this model based simply on more rapid proliferation of hepatocytes, which would be important in EGFR tumor patients undergoing major hepatic resection or LDLT. The ability of CO to preserve liver synthetic function after PHTx is potentially important in patients undergoing major hepatectomy or transplantation, particularly from expanded criteria donors. The exact source of changes in phosphorous that was observed is unclear, but could be related to better overall liver metabolic function as an indicator of mitochondrial stability and health, adenosine triphosphate (ATP) generation, 上海皓元医药股份有限公司 and/or potentially biogenesis,

which has been observed in the heart in response to CO.49 Although we observed no measurable change in ATP levels in the liver (data not shown), CO did induce a dramatic increase in expression of prohibitin in the liver, which is a mitochondrial-specific protein important in proliferation and overall mitochondrial morphology and function (Supporting Fig. 1). CO, administered as an inhaled gas, is unlikely to impact sinusoidal tone given its poor vasoreactivity, although this was not measured in this model. Mori et al.22 showed effects of CO on liver sinusoidal tone using much greater amounts of CO (4 μM versus 200 nM used here). It is also certainly possible that selective regions of the liver microvasculature may be influenced by CO, leading to improved tissue perfusion and, thereby, modulation of the proliferative response. Following PHTx, two signaling pathways are activated, a growth factor-mediated pathway and a cytokine-regulated pathway, are known to be activated.